CZ20001736A3 - Process for preparing citalopram - Google Patents

Abstract

A method for the preparation of citalopram is described comprising reaction of a compound of Formula (IV) wherein R<1> is H or C1-6alkylcarbonyl successively with a Grignard reagent of 4-halogen-fluorophenyl and a Grignard reagent of 3-halogen-N,N-dimethylpropylamine, effecting ring closure of the resulting compound of Formula (VI) and converting the resulting 1,3-dihydroisobenzofuran compound to the corresponding 5-cyano derivative, i.e. citalopram.

Description

Process for producing citalopram

Technical field

The present invention relates to a process for the manufacture of the known antidepressant drug citalopram and intermediates therefor.

BACKGROUND OF THE INVENTION

Citalopram is a well known antidepressant drug that has been on the market for several years now and has the following structure:

It is a selective, centrally active inhibitor of srotonin reuptake (5-hydroxytryptamine; 5-HT) with antidepressant effects. Antidepressant effects of this compound have been described in several publications, for example J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. The compound also has other effects in the treatment of dementia and cerebrovascular diseases, see EP-A-474580.

Citalopram was first disclosed in DE 2,657,271 corresponding to US patent 4,136,193. This patent provides the production of citalopram in one way and discloses another method that can be used for the production of citalopram.

• · · * «· · · · · ·· ··· ···· ···· ······ • · ·· ··« • · · _Λ ··· ···· " ··· ··· · «··

According to the process described, the corresponding 1- (4-fluorophenyl) 1,3-dihydro-5-isobenzofurancarbonitrile is reacted with 3- (N, N-dimethylamino) propyl chloride in the presence of methylsulfinylmethide as a condensing agent. The starting material was prepared from the corresponding

Of the 5-bromo derivative by reaction with cuprous cyanide.

According to this method, which is only given generally, citalopram can be obtained by ring closure of the compound

in the presence of a dehydrating agent and subsequent exchange of the group with 5-bromo copper (I) cyanide. The starting material of formula (II) is obtained from 5-bromophthalide by two consecutive Grignard reactions, i.e. with 4-fluorophenylmagnesium chloride or N, N-dimethylaminopropylmagnesium chloride.

A new and surprising method and intermediate for the production of citalopram have been described in U.S. Pat. 4,650,884, according to which the intermediate of formula

F

- 3 closes the ring by dehydration with strong sulfuric acid to obtain citalopram. The intermediate of formula III was prepared from 5-cyanophthalide by two consecutive Grignard reactions, i.e. with 4-fluorophenylmagnesium chloride or N, N-dimethylaminopropylmagnesium chloride.

Finally, methods for making the individual enantiomers of citalopram are also described in U.S. Pat. No. 4,943,590, which also implies that ring closure of the intermediate of formula III can be carried out with a labile ester using a base.

It has now surprisingly been found that citalopram can be produced by a novel convenient and safe process using conventional starting materials.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for the production of citalopram, comprising the following steps:

a) reacting the compound of formula IV

wherein R ¹ is hydrogen or C 1-6. ₆ alkylcarbonyl, with 4-halofluorophenyl Grignard reagent;

(b) the compound of formula (V) obtained;

wherein R ¹ is as defined above is reacted with the Grignard reagent of 3-halo-N, N-dimethylpropylamine;

c) ring closure of the compound of formula VI obtained

ch ₃ i

Wherein R ¹ is as defined above and

d) the compound of formula VII obtained

wherein R ¹ is as defined above is converted to the corresponding 5-cyano derivative, i.e. citalopram, which is isolated in the form of a base or a pharmaceutically acceptable salt.

• · · ·

- 5 - In another embodiment intermediates of formula V. provides presented invention new In another embodiment intermediates of formula VI. provides presented invention new In another embodiment intermediates of formula VII. provides presented invention new In yet another embodiment, the present invention relates an antidepressant pharmaceutical composition comprising

citalopram produced by the process of the invention.

In the specification and claims, the term C 1-6 alkyl refers to a branched or unbranched alkyl group having 1 to 6 carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl- 2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.

The Grignard reagents of 4-halofluorophenyl which may be used in step a) are magnesium halides such as chloride, bromide or iodide. Magnesium bromide is preferably used.

The 3-halo-N, N-dimethylpropylamine Grignard reagents which may be used are magnesium halides such as chloride, bromide or iodide, preferably magnesium bromide. Preferably, the two reactions are carried out sequentially without isolation of the intermediate.

The ring closure of the compound of formula (VI) may be accomplished by acid, or when R ^{1 is} C 1-6. ₆ alkylcarbonyl, may alternatively be carried out via a labile ester with a base. The acid ring closure is performed with an inorganic acid such as sulfuric acid or phosphoric acid or an organic acid such as methylsulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid. The ring closure is generally carried out via a labile ester such as methanesulfonyl-, p-toluenesulfonyl-, 10-camphorsulfonyl-, trifluoroacetyl- or trifluoromethanesulfonyl ester with the addition of a base such as triethylamine, dimethylaniline or pyridine. The basic reaction is carried out in an inert reaction

6 solvents with cooling, especially at 0 ° C, and is preferably carried out in a single reactor, for example by esterification and concomitant addition of a base.

Where R ¹ is hydrogen, conversion of R ¹ -NH to cyano is preferably carried out by diazotization followed by reaction with a CN 'ion. Most preferably, NaNC > 2 and CuCN and / or NaCN are used. When R &lt; ¹ &gt; is C1-6 alkylcarbonyl, it is initially hydrolyzed to give the corresponding compound in which R &lt; ¹ &gt; is a hydrogen atom, which is converted to other materials as described above. The hydrolysis can be carried out either in an acidic or basic medium.

The process of the invention may be carried out with or without isolation of intermediates.

The process of the invention can also be used to produce the active (S) -enantiomer of citalopram. In this case, the compound of formula VI is separated into the optically active enantiomers in an analogous manner to that described in US Patent No 4,943,590 to obtain the (S) enantiomer of the compound of formula VI, which is used in the ring closure reaction in step c). The individual enantiomers of intermediates of formulas VI and VII are also included within the meaning of these equations.

Other reaction conditions, solvents and the like are those commonly used for such reactions and can be readily determined by one of ordinary skill in the art.

The starting material of formula IV wherein R ¹ is hydrogen is commercially available and can be prepared by known methods (Tirouffet, J .; Bull. Soc. Sci. Bretagne 26, 1959, 35) and compounds wherein R ¹ is acyl. they may be made from an amino compound (R ¹ represents a hydrogen atom) by conventional acylation.

In one embodiment of the invention, R ¹ is C 1-6 alkylcarbonyl, especially methyl, ethyl, propyl, or butylcarbonyl.

In another embodiment of the invention, R ¹ is hydrogen.

• · · · · · · *.. ·.... · · · ···· · · · ·

The compound of formula (I) may be used as the free base or as a pharmacologically acceptable acid addition salt thereof. Salts formed with organic or inorganic acids may be used as acid addition salts. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, citric, citric, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic as well as with 8-halotheophyllins, for example 8-bromotheophyllin. Examples of inorganic acids are salts with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The acid addition salts of the compounds of the invention may be prepared by known methods. The base is reacted with either a calculated amount of acid in a water miscible solvent such as acetone or ethanol followed by isolation of the salt by concentration and cooling or with an excess of acid in a water immiscible solvent such as ethyl ether, ethyl acetate or dichloromethane and spontaneous salt separation.

The pharmaceutical compositions of the invention may be administered by any suitable route and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of conventional sterile injectable solutions.

The pharmaceutical compositions of the invention may be manufactured by conventional methods. For example, tablets may be prepared by mixing the active ingredient with conventional excipients and / or carriers and subsequently compressing the mixture in conventional tabletting machines. Examples of excipients or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. It may also be: - - - - - - - - - - - - - - - - - - - - -

- any excipient or additive such as coloring, flavoring, preservative, etc., provided that they are compatible with the active ingredients.

Solutions for injections may be made by dissolving the active ingredient and possible additives in a portion of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling into suitable ampoules or vials. Any suitable other commonly used additive such as an osmotic pressure adjuster, preservatives, antioxidants and the like can be added.

The process of the invention is further illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4-Dimethylamino-1- (4-amino-2-hydroxymethylphenyl) -1- (4-fluorophenyl) butan-1-ol

A solution of 4-fluorophenylmagnesium bromide made from 4-fluorobromobenzene (116 g, 0.66 mol) and magnesium turnings (20 g, 0.8 mol) in dry THF (500 mL) was added dropwise to a suspension of 520-aminophthalide (30 mL). g, 0.2 mol) in dry THF (500 mL). The temperature is kept below 5 ° C. After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 h.

A second Grignard solution made from 3-dimethylamino-propyl chloride (25 g, 0.2 mol) and magnesium turnings (6 g, 0.25 mol) in dry THF (150 mL) was added to the reaction mixture. The temperature is kept below 5 ° C during the addition. Stirring is continued for 0.5 h, then discontinued and the mixture is left at room temperature overnight.

The reaction was quenched with ice water (1000 mL) and acetic acid (60 g). THF was evaporated in vacuo. The aqueous phase is washed with ethyl acetate.

(2 χ 200 ml). NH ₄ OH was added to the aqueous phase to obtain a final pH of 9. The aqueous layer was extracted with ethyl acetate (2 x 200 mL), and the organic phase was filtered and washed with water (100 mL). Evaporation of the solvents in vacuo gave the title compound (38.8 g, 58%) as an oil.

¹ H NMR (CDCl 3, 500 MHz): 1.45-1.55 (1H, m), 1.65-1.75 (1H, m), 2.2 (6H, s), 2.27 ( 1H, m), 2.33 (2H, m), 2.43 (1H, m), 3.6-3.7 (2H, _NH2), 3.97 (1H, d, J = 12.5 Hz) 4.25 (1H, J = 12.5Hz), 6.58 (1H, d, J = 8Hz), 6.62 (1H, s), 6.95 (2H, t, J = 8.5 Hz), 7.25 (1H, d, J = 8Hz), 7.45 (2H, dt, J = 1.2Hz, J = 8.5Hz).

5-Amino-1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran

The crude 4-dimethylamino-1- (4-amino-2-hydroxymethylphenyl) -1- (4-fluorophenyl) butan-1-ol was dissolved in H 3 PO 4 (60%, 140 g) and heated at 80 ° C for 2 h. The reaction mixture was poured into ice water (1000 mL). NH 4 OH was added to give a final pH of 9. The aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic phase was filtered, washed with water (100 mL) and dried (MgSO ₄ , 10 g). The solvent was evaporated in vacuo. The title compound is obtained as an oil.

¹ H NMR (CDCl 3, 250 MHz): 1.3-1.5 (2H, m), 2.05-2.3 (10H, s + m), 3.6-3.7 (2H, NH) ₂ ), 5.0 (1H, s), 6.45 (1H, d, J = 1.8Hz), 6.55 (1H, dd, J = 8Hz, J = 1.8Hz), 95 (2H, t, J = 8.5Hz), 7.05 (1H, d, J = 8Hz), 7.45 (2H, dt, J = 1.2Hz, J = 8.5Hz).

1- (3-Dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile

5-Amino-1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydro-isobenzofuran (18 g, 0.06 mol) was dissolved in water (100 mL) and H ₂ SO ₄ ( 8 ml). NaNO ₂ (4.1 g, 0.06 mol) was dissolved in water (20 mL) and added dropwise at a temperature below 5 ° C. The diazotized solution is agitated.

- 10 0.5 hours at 0 to 5 ° C. The pH was adjusted to 6.5 by addition of a saturated solution of NasCO. This solution was added to a mixture of water (100 mL) and toluene (120 mL) containing CuCN (6 g, 0.067 mol) and NaCN (10 g, 0.2 mol) at 50-60 ° C. Stirring is continued for 0.5 h. The phases are separated and the aqueous phase is further extracted with toluene (100 mL). The combined organic phase was washed with NaCN (10% aqueous solution, 2 x 50 mL). The solvent was removed in vacuo and the residue was chromatographed on silica gel (ethyl acetate: n-heptane: triethylamine; 85: 10: 5) to give the title compound (6 g, 32%) as an oil.

¹ H NMR (CDCl ₃ , 250 MHz): 1.35 (1H, m), 1.45 (1H, m), 2.1 (6H, s), 2.15-2.25 (4H, m) 5.12 (1H, d, J = 12.5Hz), 5.18 (1H, d, J = 12.5Hz), 7.00 (2H, t, J = 8.5Hz), 7 4 (2H, t, J = 8.5Hz), 7.45 (1H, d, J = 7.5Hz), 7.5 (1H, s), 7.58 (1H, d, J) = 7.5 Hz).

Example 2

4-Dimethylamino-1- (4-acetylamino-2-hydroxymethylphenyl) -1- (4-fluorophenyl) butan-1-ol

A solution of 4-fluorophenylmagnesium bromide made from 4-fluoro-bromobenzene (11.6 g, 0.067 mol) and magnesium shavings (2 g, 0.08 mol) in dry THF (50 mL) was added dropwise to a suspension of 5acetylaminophthalide (5 g, 0.03 mol) in dry THF (50 ml). The temperature is kept below 5 ° C. After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 h.

A second Grignard solution made from 3-dimethylaminopropyl chloride (3.7 g, 0.03 mol) and magnesium shavings (0.87 g, 0.036 mol) in dry THF (15 mL) was added to the reaction mixture. The temperature is kept below 5 ° C during the addition. Stirring is continued for 0.5 h, then stopped and the mixture is left at room temperature overnight. The reaction was quenched with ice water (100 mL) and acetic acid (6 g). THF was evaporated in vacuo. The aqueous phase was washed with ethyl acetate (2 x 50 mL).

• · · ♦ · * · · · · · · · · · * * * * * * * * * * * * * * · · · ··

NH ₄ OH was added to the aqueous phase to obtain a final pH of 9. The aqueous layer was extracted with ethyl acetate (2 x 50 mL) and the organic phase was filtered and washed with water (50 mL). Evaporation of the solvents in vacuo gave the title compound ( 6.6 g, 63%) as an oil.

¹ H NMR (DMSO-d 6, 500 MHz): 1.15-1.22 (1H, m), 1.40-1.50 (1H, m), 2.02 (9H, s + s), 2 0.5 (1H, m), 2.13 (2H, m), 2.20 (1H, m), 3.95 (1H, d J = 12.5 Hz) 4.48 (1H, d J = 12) 5 Hz), 7.05 (2H, t, J = 8.5 Hz), 7.14 (2H, dd J = 8.5 Hz J = 1.2Hz), 7.47 (1H, d J = 8 Hz), 7.5 δ (1H, s), 7.64 (1H, d J = 8.5 Hz).

Claims (17)

PATENT CLAIMS 7> V * looo - ΊΊ · 3> & A process for the production of citalopram comprising the steps of: a) reacting the compound of formula IV Wherein R ¹ is hydrogen or C 1-6. ₆ alkylcarbonyl, with 4-halofluorophenyl Grignard reagent; b) the compound of formula V obtained Wherein R ¹ is as defined above is reacted with the Grignard reagent of 3-halo-N, N-dimethylpropylamine; c) ring closure of the compound of formula VI obtained Wherein R ¹ is as defined above and d) the obtained compound of formula VII wherein R ¹ is as defined above is converted to the corresponding 5-cyano derivative, i.e. citalopram, which is isolated in the form of a base or a pharmaceutically acceptable salt. The process according to claim 1, wherein the corresponding starting materials are used to obtain a compound wherein R ¹ is a hydrogen atom. The process according to claim 1, wherein the corresponding starting materials are used to obtain a compound wherein R ¹ is C 1-6. _with alkylcarbonyl. - 14 A process according to claim 3, characterized in that the corresponding starting materials are used to obtain a compound wherein C 1-6. C _1-6 alkyl is methyl, ethyl, propyl or butyl. Process according to one of Claims 1 to 4, characterized in that magnesium halide, preferably chloride, bromide or iodide, is used as the Grignard reagent. The process according to claim 5, characterized in that magnesium bromide is used as the Grignard reagent in step a). The process according to claim 5, characterized in that magnesium chloride is used as the Grignard reagent in step b). Process according to any one of claims 1 to 7, characterized in that the ring closure of the compound of formula VI is carried out by acidic ring closure by an inorganic acid such as sulfuric or phosphoric acid or an organic acid such as methylsulfonic, ptoluenesulfonic or trifluoroacetic acid. The process according to claim 3, characterized in that the ring closure of the compound of formula VI is effected by alkaline ring closure via a labile ester, preferably with simultaneous esterification and base addition. - 15 • ··· * ·· Β · and · · * · · · · « Process according to Claim 9, characterized in that the labile ester used is methanesulfonyl-, p-toluenesulfonyl-, 10-camphorsulfonyl-, trifluoroacetyl- or trifluoromethanesulfonyl ester and triethylamine is used as the base, 5 dimethylaniline or pyridine. Process according to claim 2, characterized in that the conversion of the group R ¹ -NH- to cyano is carried out by diazotization followed by reaction with CN ions. 12. The method according to claim 3, characterized in, that the conversion of the group R @ ¹ --NH-- into cyano is performed by hydrolysis Ci_s alkylcarbonylamino, R ¹ -NH-, to the corresponding amino group wherein R ¹ represents 15, and then diazotization and reaction with CN 'ions are performed. Process according to any one of claims 1 to 12, characterized in that, before being used in the ring closure reaction in step c), the compound of formula VI 20 resolved into the optically active enantiomers to yield the (S) enantiomer. 14. A compound of formula V F Formula V fc fc 9 - 16 ·· I «« 9 »« · 9 · 9 · < Wherein R ¹ represents a hydrogen atom or an alkylcarbonyl. A compound of formula VI wherein R ¹ is hydrogen or C 1. ₆ alkylcarbonyl. A compound of formula VII wherein R ¹ is hydrogen or C 1-6. ₆ alkylcarbonyl. Pharmaceutical composition with antidepressant effects, characterized in that it contains citalopram produced by the process according to any one of claims 1 to 13.